In the United States there will be at least an estimated 217,000 new cases of prostate cancer, and over 32,000 deaths as a result of prostate cancer this year. Treatment of advanced prostate cancer is limited by the development of resistance to antiandrogen therapy. Androgen receptors (AR), as well as other sex steroid binding receptors, such as the estrogen receptor (ER) and progesterone receptor (PR) have been previously classified as type I nuclear receptors. Castrate-resistant prostate cancer (CRPC) is commonly associated with increased AR gene expression, which can occur through AR gene amplification or other mechanisms. Elevated AR expression is necessary and sufficient to confer resistance to antiandrogen therapy in mouse xenograft models. In addition, first generation AR antagonists such as bicalutamide (also called Casodex®) or flutamide demonstrate agonist properties in cells engineered to express higher AR amounts. The partial agonism of these compounds is a potential liability, best illustrated clinically by the antiandrogen withdrawal response in which serum concentrations of prostate specific antigen (PSA) decline in patients after discontinuation of either of these AR antagonists. Collectively, these findings implicate increased AR expression as a molecular cause of drug resistance and suggest that second generation antiandrogens and nuclear receptor modulators might be identified by their ability to retain antagonism in cells expressing excess AR.
In view of the foregoing, there currently exists an unmet need for therapy for cancer, particularly prostate cancer, and more particularly, advanced castrate-resistant prostate cancer.